The long term goals of this research are to define and characterize molecular mechanisms by which mutations in proteins cause neurodegenerative disease and to identify pharmacological agents that ameliorate disease symptoms stemming from the accumulation of unfolded protein intermediates in neural cells. The accumulation of unfolded proteins in intracellular compartments is thought to underlie pathogenesis for a number of neurodegenerative diseases, including ALS, Parkinson, Huntington and Alzheimer diseases. More recently, the unfolded protein response has also been implicated in the pathophysiology of metabolic syndrome (diabetes/obesity/insulin resistance/cardiovascular disease), which significantly increases the impact of our work because unfolded diseases may be relevant to more than 6% of Americans. Two key components of our research have been the availability of well-defined mouse models for genetic manipulation, such as gene ablation or the introduction of heterologous transgenes, and the willingness of patients with unfolded protein disease to be involved in clinical studies. In this application, we will continue our work with patients to measure several clinical metrics from MRI and correlate these with disease severity. In addition, we will generate a novel mouse model on unfolded protein disease that will allow us to extend our understanding of the pathophysiology of unfolded protein disease. Specific Aim#1: we will develop a novel in vivo mouse model in which the unfolded protein response can be followed in real time, in individual cells, in vivo. This model will allow us to identify novel gene targets of UPR-induced transcription factors. Currently, several targets have been identified from in vitro cells in culture;however, we find that the data from in vivo experiments often contradict in vitro studies. Our paradigm will enable us to characterize the temporal sequence of events that generate the pathophysiology of neurodegeneration associated with protein trafficking defects in oligodendrocytes.